It is commonly acknowledged that estrogen and the estrogen receptors (ERs) play essential roles in the development of breast tumors, although the precise mechanisms involved have not been determined. Several treatment regimens for breast cancer have been developed that utilize Selective Estrogen Receptors Modulators (SERMs). Tamoxifen, a “first generation” SERM, (FIG. 7A) was developed more than 30 years ago and was approved by the Food and Drug Administration in 1985 for the treatment of breast cancers.
Tamoxifen antagonizes or mimics the effect of estrogen in a variety of tissues. For example, tamoxifen acts as an antiestrogen in breast tissues and CNS system, and exerts estrogenic effects in bone, cardiovascular and endometrium tissues. In bone system, it initially was suspected that tamoxifen's antiestrogenic effects might accelerate bone resorption and increase the risk of developing osteoporosis. However, in vitro and in vivo studies have demonstrated that tamoxifen performs as an estrogen in bone, promoting maintenance of bone density, and is thus useful in the treatment of osteoporosis.
Although tamoxifen shows some beneficial estrogenic effects, it also has been proposed to promote uterus and liver carcinogenesis. Some tumors become resistant to treatment with tamoxifen over time. Only a few tamoxifen alternatives have been developed, e.g. Toremifene, GW 5638 and Idoxifene, and second generation SERMs such as Raloxifene, which is currently in clinical trials. Unfortunately, it appears that raloxifene may display cross-resistance to tamoxifen resistant tumors.
Estrogen receptors also play a role in prostate cancer, and in the development of osteoporosis. Thus, agents that modulate estrogen-receptors may also be useful for the treatment of those diseases.
There is thus an ongoing need to develop new compounds for the treatment of diseases related to estrogen receptor function, in particular for the treatment of breast and prostate cancer, and osteoporosis. This need is particularly acute in light of the tendency of tumors to become resistant to treatment with therapeutic agents after extended use, and in view of the desirability of discovering compounds with reduced deleterious side effects than those exhibited by currently known compounds.